SUMMARY Kaposi?s sarcoma-associated herpesvirus (KSHV) is a major cause of cancer in the context of HIV/AIDS. We recently showed that KSHV-transformed primary effusion lymphoma (PEL) cell lines exhibit a strong requirement for the cellular lymphoid transcription factor IRF4. This finding places PEL into an emerging group of blood cancers where IRF4 is a key oncogenic driver. A detailed understanding of the oncogenic roles of IRF4 has not been achieved in any of these cancers, but evidence suggests that IRF4 functions as a master transcription factor that induces extensive epigenetic and transcriptional reprogramming. In PEL, IRF4 is required for overexpression of the MYC oncogene, but how KSHV controls IRF4, the molecular mechanism by which IRF4 regulates MYC, and whether IRF4 acts solely through MYC or has additional oncogenic roles is unknown. The long-term objective of this proposal is to determine the downstream effects that underlie the oncogenic roles of IRF4 in PEL and to use our results to develop novel therapeutic strategies. The central hypothesis of this proposal is that KSHV-induced, IRF4-dependent oncogenic transcriptional reprogramming is required for tumor cell survival and proliferation in PEL. This hypothesis is premised on our extensive preliminary work, which has identified both KSHV-encoded and cellular transcription factors that control IRF4 expression and function in PEL. Based on ChIP-Seq and mRNA-Seq experiments, we specifically hypothesize that IRF4, together with its viral and cellular co-factors, associates with promoters and distal cis-regulatory elements to drive an IRF4-dependent oncogenic transcription program, which involves both the silencing of ?toxic? tumor suppressors and the overexpression of several essential survival genes, including MYC, but also others. To test our hypothesis, we propose two Specific Aims, i.e. we will: (1) determine which toxic genes must be silenced by IRF4 to promote PEL cell viability and proliferation, and (2) determine which IRF4-stimulated genes are essential IRF4 effectors in PEL cells. Several of the already identified candidates for IRF4 effectors are high-confidence drug targets. We will therefore exploit our results in both aims to identify and test novel therapeutic strategies, in vitro and in vivo. This work uses a cutting-edge approach that integrates hypothesis-driven experiments with unbiased functional genomics approaches. The proposed study is innovative, because the oncogenic outcome of transcriptional reprogramming in the context of KSHV-associated malignancies has not been studied. The proposed work is significant, because it will uncover oncogenic roles of IRF4 in KSHV-mediated B cell proliferation and survival. In addition, results will inform our understanding of IRF4 in B cell biology and its oncogenic role in several hematopoietic malignancies. Results will be impactful, because our studies of IRF4 dependency are expected to result in improved strategies for therapeutic intervention in this incurable cancer.